New anti AIDS medication
bob
By Brian Boyle, MD
Kaletra (lopinavir/ritonavir), the newest protease inhibitor (PI) to
receive FDA approval, has been shown in studies to achieve potent and
durable virologic suppression in treatment naïve patients and in most
treatment-experienced patients who have not developed more than 5
Kaletra-related mutations.
A previous trial involving multiple PI-experienced patients indicated
that mutations in the protease gene that result in amino acid
substitutions at positions 10, 20, 24, 46, 53, 54, 63, 71, 82, 84 and
90 play a significant role in Kaletra resistance, but that more than
five of these mutations are required for the development of clinically
significant phenotypic resistance.
In order to better characterize the mutational patterns associated
with resistance to Kaletra, researchers genotyped and phenotyped HIV
isolates from 27 single and multiple PI-experienced patients with
viral loads greater than 1,000 copies/mL while on treatment with
Kaletra. Nine of these twenty-seven patients developed additional
PI-related mutations while on Kaletra. Of the 9 patients, five were
single and four were multiple PI-experienced, but at baseline all 9
had at least four protease mutations associated with reduced
susceptibility to Kaletra.
The rebound isolates from these patients displayed 1-6 new mutations,
the most common of which were at positions 10, 33, 46, 54 and 82.
Further, a new mutation at position 10, 20, 24, 33, 36, 46, 50, 53,
54, 63, 71, 82 and/or 88 was observed relative to baseline in at least
one rebound isolate. The development of these mutations was associated
with an incremental decrease in viral susceptibility to Kaletra from a
median of 5.2-fold (range 0.7- to 26-fold) at baseline (relative to
wild type) to 53-fold (range 24- to 252-fold) at the time of viral
rebound.
All nine rebound isolates remained relatively susceptible (<10 fold
increase in phenotypic resistance) to Agenerase (amprenavir) when
evolution of reduced susceptibility to lopinavir was initially
documented; however, high-grade Agenerase resistance developed in HIV
isolates from two patients who continued on Kaletra therapy despite
ongoing viral replication.
Based upon these data, the authors concluded, "Viruses from single or
multiple PI experienced patients with viral rebound during continued
[Kaletra] therapy evolve additional mutations, leading to further
decreased susceptibility to [Kaletra]. Mutations at positions 10, 46,
54 and 82 appeared most commonly in the rebound isolates. The
additional presence of mutations at positions 20, 24, 33, 50 or 53
appears to contribute to higher levels of phenotypic resistance."
These data expand the information available to clinicians regarding
the development and evolution of Kaletra resistance. Further, they
reinforce a concept most HIV clinicians are quite familiar with, that
is, that continuing a failing regimen generally results in the
development of additional viral resistance that may significantly
limit future treatment options.
6/27/01
Reference
A Molla and others. Patterns of resistance to lopinavir in
PI-experienced patients following viral rebound during
lopinavir/ritonavir therapy. 5th International Workshop on HIV Drug
Resistance and Treatment Strategies. June 4-8, 2001, Scottsdale,
Arizona.